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US20130310574A1 - Process for the Preparation of N-Monosubstituted beta-Amino Alcohols - Google Patents

Process for the Preparation of N-Monosubstituted beta-Amino Alcohols Download PDF

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US20130310574A1
US20130310574A1 US13/950,412 US201313950412A US2013310574A1 US 20130310574 A1 US20130310574 A1 US 20130310574A1 US 201313950412 A US201313950412 A US 201313950412A US 2013310574 A1 US2013310574 A1 US 2013310574A1
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proton acid
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addition salt
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Dominique Michel
Rudolf Fuchs
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Chiral Quest Suzhou Co Ltd
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Lonza AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • the invention relates to a process for the preparation of N-monosubstituted ⁇ -amino alcohols of formula
  • N-Monosubstituted ⁇ -amino alcohols of formula I like (S)-( ⁇ )-3-N-methylamino-1-(2-thienyl)-1-propanol (LY293628) are useful key intermediates and building blocks for the preparation of pharmaceutically active compounds like (S)-(+)-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine ((S)-duloxetine) (Liu, H. et al., Chirality 12 (2000) 26-29), a potential neuro-active compound which strongly inhibits the serotonine and norephedrine uptake (Deeter, J. et al., Tetrahedron Lett. 31 (1990) 7101-7104).
  • amine or “amines” include their corresponding addition salts of proton acids.
  • EP-A 457 559 and EP-A 650 965 disclose the preparation of N,N-dimethyl ⁇ -amino alcohols via Mannich-type reactions of methyl ketones with paraformaldehyde and dimethylamine followed by reduction of the carbonyl group. After reaction of the hydroxyl group affording alkyl or aryl ether derivatives one methyl radical is removed to obtain N-monosubstituted compounds which requires delicate and expensive reactions.
  • the problem to be solved was to provide an alternative and efficient process for the synthesis of N-monosubstituted ⁇ -amino alcohols and derivatives thereof in high yields. Furthermore, the proposed process should provide high yields independently of steric aspects of the used amino or carbonyl compounds.
  • the present invention discloses a process for the preparation of a compound of formula
  • R 1 and R 2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises the steps of a) reacting a mixture comprising
  • R 1 and R 2 can independently represent
  • R 1 represents furanyl or thienyl.
  • R 2 represents linear or branched C 1-8 alkyl. More particularly preferred R 2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or ten-butyl.
  • the compound of formula V is used as a free amine and/or an addition salt of a proton acid.
  • Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides.
  • the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV.
  • the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2.
  • the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof.
  • Particularly preferred alcohols are linear or branched aliphatic C 1-12 alcohols, cycloaliphatic C 5-8 alcohols, di- and/or trimeric ethylene glycols or mono C 1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.
  • Examples for said alcohols are methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl
  • said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.
  • the proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, H 1 , H 2 SO 4 and H 3 PO 4 .
  • the proton acid can be an acidic salt of a polybasic organic or inorganic acid like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates.
  • the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr.
  • reaction step a) is carried out either with added addition salts of amines or proton acids, since even distilled free ⁇ -amino ketones of formula II tend to decompose and form by-products while stored, whereas the corresponding additions salts can be stored over a longer period without decomposition.
  • the ratio of free amine and its salt corresponds to the ratio of added addition salts of amines and proton acids to the whole amine amount during reaction step a).
  • the pressure during reaction step a) is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar.
  • the inventive process In contrast to Becker et al. the inventive process generally allows direct preparation of N-monosubstituted ⁇ -keto amines and addition salts of proton acids thereof.
  • the products obtained by the inventive process can be reduced or subsequently reacted without further conversion into other salts.
  • the present invention also provides a compound of formula
  • R 1 represents furanyl, benzofuranyl, isobenzofuranyl, thienyl or benzo[b]thienyl, each being optionally substituted with halogen, linear or branched C 1-4 alkyl, linear or branched C 1-4 alkoxy, C 3-6 cycloalkyl, CF 3 , C 2 F 5 , OCF 3 or OC 2 F 5 , and wherein R 2 is selected from the group consisting of linear or branched C 1-8 alkyl, C 3-8 cyclo-alkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C 1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, furanyl, benzofuranyl, thienyl
  • the present invention also provides a compound of formula
  • R 4 represents methyl, ethyl, isobutyl and tert-butyl.
  • the present invention also provides a compound of formula
  • the present invention also provides a compound of formula
  • the present invention also provides a process for the preparation of a compound of formula
  • R 1 and R 2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises reacting a mixture comprising
  • R 1 and R 2 independently represent
  • R 1 represents furanyl or thienyl. It is also particularly preferred that R 2 represents linear or branched C 1-8 alkyl. More particularly preferred R 2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • the compound of formula V can be used as a free amine and/or an addition salt of a proton acid thereof.
  • Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides.
  • the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV.
  • the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2.
  • the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof.
  • Particularly preferred alcohols are linear or branched aliphatic C 1-12 alcohols, cycloaliphatic C 5-8 alcohols, di- and/or trimeric ethylene glycols or mono C 1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.
  • Examples for said alcohols are methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl
  • said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.
  • the proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H 2 SO 4 and H 3 PO 4 .
  • the proton acid is an acidic salt of a polybasic organic or inorganic acids like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates.
  • the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr.
  • the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar.
  • a mixture of methyl ketone (1 equivalent (eq)), primary alkyl amine and/or an addition salt thereof (1.1 to 1.5 eq), formaldehyde (1.4 to 1.5 eq), a solvent, optionally in the presence of a proton acid, is heated in an autoclave at a total pressure above 1.5 bar for 5 to 24 hours. Afterwards, the reaction solution is cooled to 20° C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product.
  • the suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 50 and 75%.
  • the product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary. If the stability of the free base is sufficient at ambient conditions, extracting with an organic solvent and an aqueous base affords the free base.
  • a mixture of methyl ketone (1 eq), primary alkyl amine and/or an addition salt thereof (1 to 1.5 eq), formaldehyde (1.0 to 1.5 eq), optionally in the presence of a proton acid, is heated in refluxing solvent for 5 to 24 hours. Afterwards, the mixture is cooled to 20° C.
  • the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product.
  • the suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 30 and 45%.
  • the product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary.
  • 2-Acetylthiophene (25.5 g, 200 mmol); methylamine hydrochloride (14.9 g, 220 mmol, 1.1 eq); paraformaldehyde (8.2 g, 280 mmol, 1.4 eq); HCl cone. (1.0 g); ethanol (100 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (50 mL) in vacuo; addition of ethyl acetate (200 mL); ca. 71% yield.
  • 2-Acetylthiophene (24.9 g, 197 mmol); methylamine hydrochloride (14.8 g, 219 mmol, 1.1 eq); paraformaldehyde (8.3 g, 276 mmol, 1.4 eq); HCl conc. (1.1 g); isopropyl alcohol (100 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; addition of isopropyl alcohol (50 mL); ca. 65% yield.
  • 2-Acetylthiophene (7.9 g, 300 mmol); methylamine hydrochloride (30.4 g, 450 mmol, 1.5 eq); paraformaldehyde (12.6 g, 420 mmol, 1.4 eq); HCl conc. (1.5 g); isopropyl alcohol (200 mL); heating under reflux (82° C.) for 8 hours; addition of ethyl acetate (200 mL); ca. 43% yield.
  • 2-Acetylthiophene (6.3 g, 50 mmol); ethylamine hydrochloride (6.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 73% yield.
  • 2-Acetylthiophene (6.3 g, 50 mmol); isobutylamine hydrochloride (8.3 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 56% yield.
  • 2-Acetylthiophene (12.6 g, 100 mmol); isobutylamine hydrochloride (16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 40% yield.
  • 2-Acetylfuran (7.5 g, 68 mmol); methylamine hydrochloride (6.9 g, 102 mmol, 1.5 eq); paraformaldehyde (3.1 g, 102 mmol, 1.5 eq); HCl conc. (1.15 g); ethanol (35 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 64% yield.
  • 2-Acetylfuran (11.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl cone. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 44% yield.
  • 2-Acetophenone (21.0 g, 175 mmol); methylamine hydrochloride (17.5 g, 263 mmol, 1.5 eq); paraformaldehyde (7.9 g, 263 mmol, 1.5 eq); HCl cone. (1.1 g); ethanol (130 mL); 115° C. for 24 hours; ca. 2 to 2.5 bar; addition of ethyl acetate (170 mL); ca. 52% yield.
  • 2-Acetonaphtone (8.5 g, 50 mmol); methylamine hydrochloride (5.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 117° C. for 14 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 60% yield.
  • 2-Acetonaphtone (17.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 5 hours; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (100 mL); ca. 42% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A process is disclosed for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00001
    • and/or an addition salt of a proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each aryl or aralkyl being optionally further substituted with alkyl, alkoxy and/or halogen.

Description

  • The invention relates to a process for the preparation of N-monosubstituted β-amino alcohols of formula
  • Figure US20130310574A1-20131121-C00002
  • and/or an addition salt of a proton acid via direct synthesis of N-monosubstituted β-keto amines of formula
  • Figure US20130310574A1-20131121-C00003
  • and/or an addition salt of a proton acid.
  • N-Monosubstituted β-amino alcohols of formula I like (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol (LY293628) are useful key intermediates and building blocks for the preparation of pharmaceutically active compounds like (S)-(+)-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine ((S)-duloxetine) (Liu, H. et al., Chirality 12 (2000) 26-29), a potential neuro-active compound which strongly inhibits the serotonine and norephedrine uptake (Deeter, J. et al., Tetrahedron Lett. 31 (1990) 7101-7104).
  • Figure US20130310574A1-20131121-C00004
  • In the following the terms “amine” or “amines” include their corresponding addition salts of proton acids.
  • Direct preparation of N-monosubstituted β-keto amines of formula II establishes an alternative and economically advantageous source for industrial production of N-monosubstituted β-amino alcohols of formula I.
  • Compounds of formula II were first synthesized in 1922 by reacting ketones with formaldehyde and primary or secondary alkylamines in the presence of hydrochloric acid (Mannich, C. et al., Chem. Ber. 55 (1922) 356-365). In said reactions with primary alkylamines formation of hydrochlorides of tertiary β-keto amines of formula
  • Figure US20130310574A1-20131121-C00005
  • prevails over formation of hydrochlorides of secondary β-keto amines of formula II. These findings were supported by Blicke et al. (J. Am. Chem. Soc. 64 (1942) 451-454) and Becker et al. (Wiss. Z. Tech. Hochsch. Chem. Leuna-Merseburg. 11 (1969) 38-41).
  • According to Mannich et al. steam destillation of tertiary β-keto amines of formula III results in formation of secondary β-keto amines of formula II in fairly satisfactory yields, accompanied by vinyl compounds and other by-products.
  • In spite of the loss of more than 50% of the starting compounds and due to lack of alternative processes this procedure is still used for the preparation of secondary β-keto amines.
  • Another drawback in presently known preparation methods of β-keto amines is the need of isolation of the desired intermediate compounds of formula II from unwanted by-products of formula III.
  • EP-A 457 559 and EP-A 650 965 disclose the preparation of N,N-dimethyl β-amino alcohols via Mannich-type reactions of methyl ketones with paraformaldehyde and dimethylamine followed by reduction of the carbonyl group. After reaction of the hydroxyl group affording alkyl or aryl ether derivatives one methyl radical is removed to obtain N-monosubstituted compounds which requires delicate and expensive reactions.
  • Only Becker et al. disclose some few examples with yields of about 60% of N-monomethyl β-keto amines using N-methylammonium oxalates as nitrogen source. Nevertheless, the process disclosed by Becker et al. is not advantageous because it strictly depends on the use of amino oxalates. In contrast to the free amines or corresponding hydrochlorides oxalates of primary amines are not commercially available and their preparation requires further synthesis and purification steps.
  • Using oxalates is also disadvantageous because it requires additional reduction equivalents in the next step, reducing the ketone intermediates to the title compounds.
  • None of the known processes for the production of N-monosubstituted β-amino alcohols of formula I and ether derivatives thereof includes, intends or concerns intermediate products comparable to N-monosubstituted β-keto amines of formula II of the present invention. Although still many efforts were made to find new preparation processes, the pathway of the present invention for direct synthesis of N-monosubstituted β-keto amines and subsequent reduction to N-monosubstituted β-amino alcohols is not yet disclosed.
  • The problem to be solved was to provide an alternative and efficient process for the synthesis of N-monosubstituted β-amino alcohols and derivatives thereof in high yields. Furthermore, the proposed process should provide high yields independently of steric aspects of the used amino or carbonyl compounds.
  • The problems mentioned above could be solved according to claim 1.
  • Starting with commercially available methyl ketones and primary amines and/or an addition salt of a proton acid, which were reacted with formaldehyde in the presence a solvent and optionally of a proton acid at a pressure above 1.5 bar N-monosubstituted β-amino ketones which could be directly reduced to the desired N-monosubstituted β-amino alcohols were obtained in high yields.
  • As a further advantage of the instant process high yields of N-monomethyl β-amino ketones can be obtained by direct usage of methylamine hydrochloride which is easily available, cheap and, since it is a solid compound, easy to handle.
  • The present invention discloses a process for the preparation of a compound of formula
  • Figure US20130310574A1-20131121-C00006
  • and/or an addition salt of a proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen, which process comprises the steps of
    a) reacting a mixture comprising
      • (i) a methyl ketone of formula
  • Figure US20130310574A1-20131121-C00007
      • wherein R1 is as defined above,
      • (ii) a compound of formula

  • H2N—R2  V
      • and/or an addition salt of a proton acid, wherein R2 is as defined above, and
      • (iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
      • a solvent selected from the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and
      • optionally a proton acid
        to afford a compound of formula
  • Figure US20130310574A1-20131121-C00008
  • and/or an addition salt of a proton acid, and
  • b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid,
  • wherein the first step is carried out at a pressure above 1.5 bar.
  • In a preferred embodiment R1 and R2 can independently represent
  • linear or branched C1-8 alkyl, C3-8 cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl or aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl,
    each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5.
  • It is particularly preferred that R1 represents furanyl or thienyl.
  • It is also particularly preferred that R2 represents linear or branched C1-8 alkyl. More particularly preferred R2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or ten-butyl.
  • Preferably, the compound of formula V is used as a free amine and/or an addition salt of a proton acid. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides.
  • In a preferred embodiment the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. Particularly preferred the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2.
  • In a preferred embodiment the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof.
  • Particularly preferred alcohols are linear or branched aliphatic C1-12 alcohols, cycloaliphatic C5-8 alcohols, di- and/or trimeric ethylene glycols or mono C1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.
  • Examples for said alcohols are methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate.
  • Preferably said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.
  • The proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, H1, H2SO4 and H3PO4. In a preferred embodiment the proton acid can be an acidic salt of a polybasic organic or inorganic acid like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates.
  • More preferably the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr.
  • Preferably reaction step a) is carried out either with added addition salts of amines or proton acids, since even distilled free β-amino ketones of formula II tend to decompose and form by-products while stored, whereas the corresponding additions salts can be stored over a longer period without decomposition. In the products, the ratio of free amine and its salt corresponds to the ratio of added addition salts of amines and proton acids to the whole amine amount during reaction step a).
  • In a preferred embodiment the pressure during reaction step a) is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar.
  • In contrast to Becker et al. the inventive process generally allows direct preparation of N-monosubstituted β-keto amines and addition salts of proton acids thereof. The products obtained by the inventive process can be reduced or subsequently reacted without further conversion into other salts.
  • The present invention also provides a compound of formula
  • Figure US20130310574A1-20131121-C00009
  • and its addition salts of proton acids,
    wherein R1 represents furanyl, benzofuranyl, isobenzofuranyl, thienyl or benzo[b]thienyl, each being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5, and
    wherein R2 is selected from the group consisting of linear or branched C1-8 alkyl, C3-8 cyclo-alkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl,
    each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5,
    with the exception of the compound wherein R1 is thienyl and R2 is benzyl.
  • The present invention also provides a compound of formula
  • Figure US20130310574A1-20131121-C00010
  • and its addition salts of proton acids, wherein R4 represents methyl, ethyl, isobutyl and tert-butyl.
  • The present invention also provides a compound of formula
  • Figure US20130310574A1-20131121-C00011
  • and its addition salts of proton acids.
  • The present invention also provides a compound of formula
  • Figure US20130310574A1-20131121-C00012
  • and its addition salts of proton acids.
  • The present invention also provides a process for the preparation of a compound of formula
  • Figure US20130310574A1-20131121-C00013
  • and/or an addition salt of a proton acid, wherein R1 and R2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each being optionally further substituted with alkyl, alkoxy and/or halogen,
    which process comprises reacting a mixture comprising
      • (i) a methyl ketone of formula
  • Figure US20130310574A1-20131121-C00014
      • wherein R1 is as defined above, and
      • (ii) a compound of formula

  • H2N—R2  V
      • and/or an addition salt of a proton acid, wherein R2 is as defined above, and
      • (iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
      • a solvent selected from the group consisting of water, aliphatic alcohols, cycloaliphatic alcohols and mixtures thereof, and
      • optionally a proton acid
        to afford a compound of formula
  • Figure US20130310574A1-20131121-C00015
  • and/or an addition salt of a proton acid, wherein R1 and R2 are as defined above, and wherein the reaction is carried out at a pressure above 1.5 bar.
  • In a preferred embodiment R1 and R2 independently represent
  • linear or branched C1-8 alkyl, C3-8 cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl,
    each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5.
  • It is particularly preferred that R1 represents furanyl or thienyl. It is also particularly preferred that R2 represents linear or branched C1-8 alkyl. More particularly preferred R2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • Preferably, the compound of formula V can be used as a free amine and/or an addition salt of a proton acid thereof. Particularly preferred are free amines, formates, acetates, oxalates, hydrochlorides, hydrobromides or mixtures thereof. More particularly preferred are free amines and/or hydrochlorides.
  • In one preferred embodiment the compound of formula V is present in an amount at least equimolar to that of the compound of formula IV. Particularly preferred the molar ratio of the compound of formula V to the compound of formula IV is between 1 and 2.
  • In a preferred embodiment the solvent comprises water, an aliphatic or cycloaliphatic alcohol or a mixture thereof.
  • Particularly preferred alcohols are linear or branched aliphatic C1-12 alcohols, cycloaliphatic C5-8 alcohols, di- and/or trimeric ethylene glycols or mono C1-4 alkyl or acetyl derivatives thereof, each of said alcohols containing 1 to 3 hydroxy groups.
  • Examples for said alcohols are methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether and triethylene glycol monoacetate.
  • Preferably said alcohol is ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, diethylene glycol or triethylene glycol.
  • The proton acid can be any organic or inorganic acid, the acid being preferably selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H2SO4 and H3PO4. In a preferred embodiment the proton acid is an acidic salt of a polybasic organic or inorganic acids like monoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkali hydrogencarbonates. More preferably the proton acid is selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, HCl and HBr, more preferably it is selected from the group consisting of formic acid, acetic acid, HCl and HBr.
  • In a preferred embodiment the pressure during the reaction is above 1.5 bar, more preferably in the range of 1.5 to 10 bar and particularly preferred in the range of 1.5 to 5 bar.
  • The present invention is illustrated by the following non-limiting examples.
    • General Procedure for Examples 1 to 8
  • A mixture of methyl ketone (1 equivalent (eq)), primary alkyl amine and/or an addition salt thereof (1.1 to 1.5 eq), formaldehyde (1.4 to 1.5 eq), a solvent, optionally in the presence of a proton acid, is heated in an autoclave at a total pressure above 1.5 bar for 5 to 24 hours. Afterwards, the reaction solution is cooled to 20° C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 50 and 75%. The product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary. If the stability of the free base is sufficient at ambient conditions, extracting with an organic solvent and an aqueous base affords the free base.
    • General Procedure for Comparative Examples 1 to 6
  • A mixture of methyl ketone (1 eq), primary alkyl amine and/or an addition salt thereof (1 to 1.5 eq), formaldehyde (1.0 to 1.5 eq), optionally in the presence of a proton acid, is heated in refluxing solvent for 5 to 24 hours. Afterwards, the mixture is cooled to 20° C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 30 and 45%. The product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary.
    • EXAMPLE 1 3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=methyl)
  • 2-Acetylthiophene (25.5 g, 200 mmol); methylamine hydrochloride (14.9 g, 220 mmol, 1.1 eq); paraformaldehyde (8.2 g, 280 mmol, 1.4 eq); HCl cone. (1.0 g); ethanol (100 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (50 mL) in vacuo; addition of ethyl acetate (200 mL); ca. 71% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.16 (2H, s, br), 8.07 (1H, dd, J=5.0, 1.0), 8.01 (1H, dd, J=3.8, 1.0), 7.29 (1H, dd, J=5.0, 3.8), 3.49 (2H, t), 3.20 (2H, t), 2.56 (3H, s).
  • 13C-NMR δ (DMSO-d6, 100 MHz): 189.9, 142.7, 135.4, 133.8, 128.8, 43.1, 34.6, 32.4.
    • EXAMPLE 2 3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=methyl)
  • 2-Acetylthiophene (24.9 g, 197 mmol); methylamine hydrochloride (14.8 g, 219 mmol, 1.1 eq); paraformaldehyde (8.3 g, 276 mmol, 1.4 eq); HCl conc. (1.1 g); isopropyl alcohol (100 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; addition of isopropyl alcohol (50 mL); ca. 65% yield.
    • COMPARATIVE EXAMPLE 1 3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=methyl)
  • 2-Acetylthiophene (7.9 g, 300 mmol); methylamine hydrochloride (30.4 g, 450 mmol, 1.5 eq); paraformaldehyde (12.6 g, 420 mmol, 1.4 eq); HCl conc. (1.5 g); isopropyl alcohol (200 mL); heating under reflux (82° C.) for 8 hours; addition of ethyl acetate (200 mL); ca. 43% yield.
    • EXAMPLE 3 3-(Ethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=ethyl)
  • 2-Acetylthiophene (6.3 g, 50 mmol); ethylamine hydrochloride (6.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 73% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.3 (2H, s, br), 8.08 (1H, dd), 8.00 (1H, dd), 7.28 (1H, dd), 3.51 (2H, t), 3.20 (2H, t), 2.96 (2H, q), 1.23 (3H, t).
    • COMPARATIVE EXAMPLE 2 3-(Ethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=ethyl)
  • 2-Acetylthiophene (12.6 g, 100 mmol); ethylamine hydrochloride (12.2 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 6 hours; removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (70 mL); ca. 31% yield.
    • EXAMPLE 4 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=isobutyl)
  • 2-Acetylthiophene (6.3 g, 50 mmol); isobutylamine hydrochloride (8.3 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 56% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.0 (2H, s, br), 8.08 (1H, dd), 7.99 (1H, dd), 7.29 (1H, dd), 3.55 (2H, t), 3.22 (2H, t), 2.78 (2H, d), 2.03 (1H, m), 0.96 (6H, d).
    • COMPARATIVE EXAMPLE 3 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=isobutyl)
  • 2-Acetylthiophene (12.6 g, 100 mmol); isobutylamine hydrochloride (16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 40% yield.
    • EXAMPLE 5 3-(tert-Butylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=tert-butyl)
  • 2-Acetylthiophene (6.3 g, 50 mmol); tert-butylamine hydrochloride (8.3 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); butanol (35 mL); 117° C. for 9 hours; ca. 2 to 2.5 bar; addition of ethyl acetate (50 mL); ca. 52% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.2 (2H, s, br), 8.08 (1H, dd), 7.98 (1H, dd), 7.30 (1H, dd), 3.54 (2H, t), 3.19 (2H, t), 1.34 (9H, s).
    • COMPARATIVE EXAMPLE 4 3-(tert-Butylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R1=thiophen-2-yl, R2=tert-butyl)
  • 2-Acetylthiophene (12.6 g, 100 mmol); tert-butylamine hydrochloride (16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl cone. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 18 hours; addition of ethyl acetate (100 mL); ca. 37% yield.
    • EXAMPLE 6 3-(Methylamino)-1-(furan-2-yl)propan-1-one hydrochloride (II, R1=furan-2-yl, R2=methyl)
  • 2-Acetylfuran (7.5 g, 68 mmol); methylamine hydrochloride (6.9 g, 102 mmol, 1.5 eq); paraformaldehyde (3.1 g, 102 mmol, 1.5 eq); HCl conc. (1.15 g); ethanol (35 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 64% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.0 (2H, s, br), 8.05 (1H, m), 7.53 (1H, m), 6.77 (1H, m), 3.34 (2H, t), 3.2 (2H, m), 2.57 (3H, s, br).
    • COMPARATIVE EXAMPLE 5 3-(Methylamino)-1-(furan-2-yl)propan-1-one hydrochloride (II, R1=furan-2-yl, R2=methyl)
  • 2-Acetylfuran (11.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl cone. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 44% yield.
    • EXAMPLE 7 3-(Methylamino)-1-phenylpropan-1-one hydrochloride (II, R1=phenyl, R2=methyl)
  • 2-Acetophenone (21.0 g, 175 mmol); methylamine hydrochloride (17.5 g, 263 mmol, 1.5 eq); paraformaldehyde (7.9 g, 263 mmol, 1.5 eq); HCl cone. (1.1 g); ethanol (130 mL); 115° C. for 24 hours; ca. 2 to 2.5 bar; addition of ethyl acetate (170 mL); ca. 52% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.2 (2H, s, br), 8.0 (2H, m), 7.7 (1H, m), 7.6 (2H, m), 3.55 (2H, t), 3.21 (2H, t), 2.59 (3H, s).
    • EXAMPLE 8 3-(Methylamino)-1-(2-naphthyl)propan-1-one hydrochloride (II, R1=2-naphthyl, R2=methyl)
  • 2-Acetonaphtone (8.5 g, 50 mmol); methylamine hydrochloride (5.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 117° C. for 14 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 60% yield.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 9.3 (2H, s, br), 8.74 (1H, s), 8.17 (1H, d), 8.0 (3H, m), 7.7 (2H, m), 3.70 (2H, t), 3.28 (2H, m), 2.60 (3H, s).
    • COMPARATIVE EXAMPLE 6 3-(Methylamino)-1-(2-naphthyl)propan-1-one hydrochloride (II, R1=2-naphthyl, R2=methyl)
  • 2-Acetonaphtone (17.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 5 hours; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (100 mL); ca. 42% yield.
    • EXAMPLE 9 3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol (I, R1=thiophen-2-yl, R2=methyl)
  • To a mixture of 3-(methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (10.3 g, 50 mmol) and ethanol (35 mL) at 4° C. sodium hydroxide (4.0 g of a 50% aqueous solution) was added in about 5 minutes. Afterwards, neat sodium borhydride (0.95 g, 25 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 5 minutes and the mixture was stirred for 10 additional minutes. Water (20 mL) was then added. Afterwards, the mixture was concentrated about 5 times under vacuum and the residue was extracted with tert-butyl methyl ether (2×20 mL). The collected organic phases were finally concentrated under vacuum affording an orange oil which crystallised spontaneously after a few hours. Finally, an orange solid was obtained (7.2 g, 84% yield). This compound can then be used without further purification.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 7.35 (1H, dd, J=4.8, 1.0), 6.94 (1H, dd, J=4.8, 3.6), 6.90 (1H, dd, J=3.6, 1.0), 4.90 (1H, t), 3.7 (2H, m), 2.56 (2H, m), 2.25 (3H, s), 1.79 (2H, q).
  • 13C-NMR δ (DMSO-d6, 100 MHz): 150.9, 126.3, 123.7, 122.3, 67.8, 48.5, 38.7, 36.0.
    • EXAMPLE 10 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-ol (I, R1=thiophen-2-yl, R2=methyl)
  • To a mixture of 3-(isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (4.2 g, 19.4 mmol) and ethanol (10 mL) at 4° C. sodium hydroxide (1.6 g of a 50% aqueous solution) was added in about 20 minutes. Afterwards, neat sodium borhydride (0.37 g, 9.7 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 20 minutes and the mixture was stirred for 10 additional minutes. Afterwards the precipitate was removed by filtration and the mixture was concentrated under vacuum affording an orange oil. The crude product was purified by column chromatography using a 40:10:1 (v:v:v) mixture of methylene chloride/methanol/ammonium hydroxide (25% aqueous solution) affording 3.1 g (76% yield) of product.
  • 1H-NMR δ (DMSO-d6, 400 MHz): 7.20 (1H, dd, J=4.8, 1.0), 6.98 (1H, dd), 6.94 (1H, dd, J=4.8, 3.6), 5.20 (1H, dd), 4.98 (2H, br), 3.02 (1H, m), 2.93 (1H, m), 2.43 (2H, symm. m), 2.03 (1H, m), 1.97 (1H, m), 1.80 (1H, sept), 0.95 (6H, d).
  • 13C-NMR δ (DMSO-d6, 100 MHz): 150.9, 126.3, 123.8, 122.5, 72.1, 57.8, 48.5, 37.4, 28.2, 20.8.

Claims (13)

1.-8. (canceled)
9. A compound of formula
Figure US20130310574A1-20131121-C00016
and its addition salts of proton acids, wherein R1 represents
furanyl, benzofuranyl, isobenzofuranyl, thienyl or benzo[b]thienyl, each being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5, OCF3 or OC2F5; and wherein R2 is selected from the group consisting of linear or branched C1-8 alkyl, C3-8 cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkyl residue is linear C1-4 alkyl, and the aryl moiety is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl being optionally substituted with halogen, linear or branched C1-4 alkyl, linear or branched C1-4 alkoxy, C3-6 cycloalkyl, CF3, C2F5 OCF3 or OC2F5 with the exception of the compound wherein R1 represents thienyl and R2 represents benzyl.
10.-11. (canceled)
12. A compound of formula
Figure US20130310574A1-20131121-C00017
and its addition salts of proton acids.
13.-20. (canceled)
21. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00018
and/or an addition salt of a proton acid, wherein R1 is selected from the group consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl, and benzo[b]thienyl and wherein R2 is selected from the group consisting of linear or branched C1-8 alkyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00019
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol and mixtures thereof, and
optionally a proton acid
to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00020
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
22. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00021
and/or an addition salt of a proton acid, wherein R1 is selected from the group consisting of furanyl and thienyl and wherein R2 is selected from the group consisting of linear or branched C1-8 alkyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00022
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, 2-butanol and mixtures thereof, and
optionally a proton acid
to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00023
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
23. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00024
and/or an addition salt of a proton acid, wherein R1 is selected from the group consisting of furanyl and thienyl and wherein R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00025
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutanol, tert-butanol, and 2-butanol and mixtures thereof, and
optionally a proton acid
to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00026
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
24. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00027
and/or an addition salt of a proton acid, wherein R1 is phenyl and R2 is methyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00028
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00029
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
25. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00030
and/or an addition salt of a proton acid, wherein R1 is thienyl and R2 is methyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00031
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00032
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
26. A process for the preparation of a compound of formula
Figure US20130310574A1-20131121-C00033
and/or an addition salt of a proton acid, wherein R1 is furanyl and R2 is methyl, which process comprises the following steps
a) reacting a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00034
wherein R1 is as defined above, and
(ii) a compound of formula

H2N—R2  (V)
and/or an addition salt of a proton acid, wherein R2 is as defined above, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00035
and/or an addition salt of a proton acid, and
b) reducing the carbonyl group of said β-amino ketone to afford a compound of formula I, and/or an addition salt of a proton acid
wherein the first step is carried out by heating the mixture to a pressure above 1.5 bar.
27. A process for the preparation of a β-amino ketone of formula
Figure US20130310574A1-20131121-C00036
and its addition salts of a proton acid, which process comprises
heating to a pressure above 1.5 bar a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00037
(ii) a compound of formula

H2N—CH3  (V)
and/or an addition salt of a proton acid, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00038
and/or an addition salt of a proton acid.
28. A process for the preparation of a β-amino ketone of formula
Figure US20130310574A1-20131121-C00039
and its addition salts of a proton acid, which process comprises
heating to a pressure above 1.5 bar a mixture comprising
(i) a methyl ketone of formula
Figure US20130310574A1-20131121-C00040
(ii) a compound of formula

H2N—CH3  V
and/or an addition salt of a proton acid, and
(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presence of
a solvent selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, and optionally a proton acid to afford a β-amino ketone of formula
Figure US20130310574A1-20131121-C00041
and/or an addition salt of a proton acid.
US13/950,412 2002-07-09 2013-07-25 Process for the preparation of N-monosubstituted β-amino alcohols Expired - Lifetime US8962865B2 (en)

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